Cachexia is a metabolic wasting syndrome that commonly affects cancer patients, and accounts for as many as 25% of cancer deaths. The root causes of cancer cachexia remain unknown, and as such there are presently no effective treatments for the disorder. We have developed the first-ever experimental system to study cancer cachexia, and we therefore propose here to use the system to discover the proteins secreted by tumors that cause the cachexia phenotype. We will use advanced proteomic approaches to identify high priority candidate proteins, and we will further validate those candidates based on their differential abundance in patient-derived plasma samples, and we will functionally validate them both in vitro and in vivo. These studies are expected to lead to the discovery of the biological basis of cachexia, and thereby establish a clear path toward the development of effective therapeutics.